The initial funding period for this grant supported an investigation which defined in part the regulation of myocardial metabolism by changing conditions of muscle length and load throughout the course of contraction. The three basic findings have been: first, during the maximum and constant level of activation achieved by myocardial tetanus, mechanical conditions have virtually no influence on metabolism; second, there is continuous metabolism during the entire isometric twitch contraction, so that both tension development early in contraction and tension maintenance later in contraction are energetically important; third, metabolism may be interrupted by externally imposed muscle shortening at any time during the isometric twitch contraction, but this effect is overridden by experimental conditions which tend to increase the intracellular calcium concentration. These findings have suggested the hypothesis that I will be able to explore with the support of this renewal application: the physiological variations in myocardial length and load that occur during the course of the normal isotonic cardiac contraction themselves serve to regulate metabolism during the course of each contraction. This hypothesis will be tested by defining in a polarographic myograph the oxygen consumption of isolated cat papillary muscles sampled incrementally throughout variably afterloaded isotonic twitch contractions. This will be done with normal and then with enhanced intracellular calcium levels. These measurements of cumulative oxygen consumption at known increments of isotonic twitch duration will allow the interaction of metabolism with active tension and normally occurring shortening to be studied in detail and define any potential feedback during contraction between changing mechanical state and myocardial energetics. Termination of metabolism at progressively later times during contraction with increasing afterloads would suggest that intrinsic muscle shortening serves as a primary regulator of metabolism during the normal heartbeat. Abolition of this control with enhanced intracellular calcium would suggest that this length-dependent metabolic regulation is mediated by calcium. Taken together, these findings would support the hypothesis.